SDF-1 (stromal cell-derived factor-1) is a protein which belongs to a CXC chemokine family containing conserved 4 cysteine residues and is recognized to have a plurality of isoforms including α, β, and γ. From 1993 to 1994, SDF-1 was discovered as a novel secretory protein produced by bone marrow stromal cells and furthermore as a protein having a growth promoting function for B-lymphoid progenitor cell clones. Thereafter in 1996, it was revealed that SDF-1 is a protein which inhibits a receptor necessary for invasion of human immunodeficiency virus (HIV) into a host cell.
It has been known that SDF-1-deficient mice die immediately after birth and present abnormalities in hematopoiesis in the bone marrow, formation of the interventricular septum or neural tissue formation. Furthermore, it has been revealed that the SDF-1 receptor is CXCR4 and the SDF-1 first among the chemokines forms a ligand-receptor relationship together with CXRC4.
One of the physiological actions of SDF-1 is a angiogenesis-inducing action. The angiogenesis-inducing action of SDF-1 is based on an action of recruiting vascular progenitor cells to an ischemic site and has been attracting attention in being a different mechanism from the angiogenesis-inducing activity due to growth factors having an intrinsic angiogenesis-inducing activity such as basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF).
To date, documents which link SDF-1 to angiogenesis have reported that SDF-1 production is induced by hypoxia-inducible factor 1 (HIF-1) produced at the ischemic site using dorsal skin-lift animal models and consequently accumulation of vascular progenitor cells at the ischemic site is caused (for example, see Nature Medicine, volume 10(8), pages 858-864 (2004)). Furthermore, it has been reported that transplantation of fibroblasts which have been genetically modified to produce SDF-1 into sites of myocardial infarction accumulates bone marrow-derived vascular progenitor cells in the infarction sites and additionally improves the cardiac function (for example, see Lancet (volume 362, pages 697-703 (2003)). It has also been reported that administration of SDF-1 genes to ischemia sites of inferior limb had resulted in observation of angiogenesis and in an increase in the blood flow volume (for example, refer to Circulation, volume 109, pages 2454-2461, (2004)).
Examples of sustained release compositions containing growth factors having a angiogenesis activity include a formulation combining bFGF with a crosslinked gelatin gel (for example, see International Publication No. WO 94/27630) or a formulation combining a hepatocyte growth factor (HGF) with a gelatin hydrogel (for example, see International Publication No. WO 2003/007982).
However, both of the above prior techniques do not teach continuous external administration of SDF-1, and there has been no safe sustained release composition which enables effective manifestation of a pharmacological action of SDF-1 and can be administered to a living body.